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The NLRP3 inflammasome plays a crucial role in the innate immune response to pathogens and exogenous or endogenous danger signals. Its activity must be precisely and tightly regulated to generate tailored immune responses. However, the immune cell subsets and cytokines controlling NLRP3 inflammasome activity are still poorly understood. Here, we have shown a link between NKT-cell-mediated TNF-α and NLRP3 inflammasome activity. The NLRP3 inflammasome in APCs was critical to potentiate NKT-cell-mediated immune responses, since C57BL/6 NLRP3 inflammasome-deficient mice exhibited reduced responsiveness to α-galactosylceramide. Importantly, NKT cells were found to act as regulators of NLRP3 inflammasome signaling, as NKT-cell-derived TNF-α was required for optimal IL-1β and IL-18 production by myeloid cells in response to α-galactosylceramide, by acting on the NLRP3 inflammasome priming step. Thus, NKT cells play a role in the positive regulation of NLRP3 inflammasome priming by mediating the production of TNF-α, thus demonstrating another means by which NKT cells control early inflammation., (© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Influenza A virus (IAV) infection results in a highly contagious respiratory illness leading to substantial morbidity and occasionally death. In this report, we assessed the in vivo physiological contribution of invariant NKT (iNKT) lymphocytes, a subset of lipid-reactive αβ T lymphocytes, on the host response and viral pathogenesis using a virulent, mouse-adapted, IAV H3N2 strain. Upon infection with a lethal dose of IAV, iNKT cells become activated in the lungs and bronchoalveolar space to become rapidly anergic to further restimulation. Relative to wild-type animals, C57BL/6 mice deficient in iNKT cells (Jα18(-/-) mice) developed a more severe bronchopneumonia and had an accelerated fatal outcome, a phenomenon reversed by the adoptive transfer of NKT cells prior to infection. The enhanced pathology in Jα18(-/-) animals was not associated with either reduced or delayed viral clearance in the lungs or with a defective local NK cell response. In marked contrast, Jα18(-/-) mice displayed a dramatically reduced IAV-specific CD8(+) T cell response in the lungs and in lung-draining mediastinal lymph nodes. We further show that this defective CD8(+) T cell response correlates with an altered accumulation and maturation of pulmonary CD103(+), but not CD11b(high), dendritic cells in the mediastinal lymph nodes. Taken together, these findings point to a role for iNKT cells in the control of pneumonia as well as in the development of the CD8(+) T cell response during the early stage of acute IAV H3N2 infection.

Although cerebral endothelium disturbance is commonly observed in central nervous system (CNS) inflammatory pathologies, neither the cause of this phenomenon nor the effective participation of blood-brain barrier (BBB) in such diseases are well established. Observations were mostly made in vivo using mouse models of chronic inflammation. This paper presents a new mouse in vitro model suitable for the study of underlying mechanistic events touching BBB functions during CNS inflammatory disturbances. This model consists of a coculture with both primary cell types isolated from mice. Mouse brain capillary endothelial cell (MBCEC)s coming from brain capillaries are in culture with their in vivo partners and form differentiated monolayers that retain endothelial markers and numerous phenotypic properties of in vivo cerebral endothelium, such as: (1) peripheral distribution of tight junction proteins (occludin, claudin-5, claudin-3 and JAM-1); (2) high trans-endothelium electrical resistance value; (3) attenuated paracellular flux of sucrose and inulin; (4) P-gp expression; (5) no MECA-32 expression. Furthermore, this endothelium expresses cell adhesion molecules described in vivo and shows intracellular cell adhesion molecule-1 and vascular cell adhesion molecule-1 upregulation under lipopolysaccharide-treatment. Therefore, this well-differentiated model using autologous cells appears as a suitable support to reconstitute pathological in vitro BBB model.

Prostaglandins (PGs) are potent eicosanoid lipid mediators derived from phospholipase-released arachidonic acid, which are involved in numerous homeostatic biological functions and inflammation. They are generated by the sequential action of cyclooxygenase isozymes and cell-specific PG synthases. Along with their role in inflammatory responses, recent accumulating evidence strongly suggests that PGs, including PGD2, are part of a complex regulatory network that modulates the immune system. PGD2 is the major prostanoid secreted by activated mast cells and has long been implicated in allergic diseases. The aim of this review is to discuss our current understanding of the mode of action of PGD2 during Th2-mediated inflammation. We also discuss recent findings, which suggest that PGD2 exerts important effects on both immune and inflammatory responses by targeting the D prostanoid receptor 1 on dendritic cells, the most potent antigen-presenting cells.

Non-obese diabetic mice spontaneously develop a type 1 diabetes. The entry of leukocytes in the islets of Langerhans was studied in untreated and in irradiated mice. FITC-labeled cells from spleen, lymph nodes or bone marrow of healthy or diabetic donors did home to the inflamed islets of unmanipulated recipients. B and T cells migrated equally well, whereas rare neutrophils entered the islets. Lymphocyte homing was blocked by anti-L-selectin and anti-α4 integrin antibodies.Insulitis transfer experiments using mice congenic at the Thy-1 locus showed that anti-α4 integrin treatment totally inhibited the migration of donor type T cells in the islets, whereas anti-L-selectin only had an early and transient effect. The expression of vascular addressins in the islets was linked to the presence of mononuclear cells. Thus, in the developing islet infiltrate, the entry of cells appears continuous and restricted to lymphocytes, whether autoreactive or not, and involves the L-selectin. This mechanism rather promotes the migration of naive-type cells. Conversely,during the adoptive transfer of insulitis the entry of L-selectin diabetogenic T cells is highly favored, to the detriment of L-selectin naive type cells. [ABSTRACT FROM PUBLISHER]